Rifaximin (INN, see The Merck Index, XIII ed., 8304, CAS No. 80621-81-4), IUPAC nomenclature (2S, 16Z, 18E, 20S, 21S, 22R, 23R, 24R, 25S, 26S, 27S, 28E)-5, 6, 21, 23, 25 pentahydroxy-27-methoxy-2, 4, 11, 16, 20, 22, 24, 26-octamethyl-2,7-(epoxypentadeca-(1,11,13)trienimino) benzofuro (4,5-e) pyrido (1,2,-a benzimidazole-1,15(2H) dione, 25-acetate) is a semi-synthetic antibiotic belonging to the class of rifampicins, more precisely it is a pyrido-imidazo rifamycin described in IT 1154655, whereas EP 0161534 describes a process for the production starting from rifamycin O (The Merck Index XIII ed., 8301).
Rifaximin is commercially available under the trademarks Normix®, Rifacol® and Xifaxan®. Rifaximin is an antibiotic that can be used locally with a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic organisms. Rifaximin is characterized by low systemic absorption and is well known for its antibacterial effect on bacteria localized in the gastrointestinal tract, for example, Escherichia coli and Clostridium difficile. Rifaximin is also used for the treatment or prevention of intestinal disorders such as traveller's diarrhoea, infectious diarrhoea, and other diarrhoea irritable bowel syndrome, known as “irritable bowel disease” (IBS), bacterial overgrowth in the small intestine also known as “small intestinal bowel overgrowth” (SIBO), Crohn's disease (CD), colitis pancreatic insufficiency, enteritis, fibromyalgia, hepatic encephalopathy functional gastrointestinal disorder, functional dyspepsia with diarrhoea and other infections, for example, vaginal infections. Rifaximin is useful as antibacterial or prophylactic prior to and/or post colon surgery, and for dysentery, paucities, peptic ulcer disease, and bacterial dysbiosis.
Solid rifaximin can be in crystalline or in amorphous form. The crystalline forms can be polymorphic, hydrate, anhydrous or solvate forms and can have different solubility, and also different in vivo absorption.
Several patent applications describe polymorphic forms of rifaximin, for instance U.S. Pat. No. 7,045,620, US 2008/0262220, U.S. Pat. No. 7,612,199, US 2009/0130201 (rifaximin forms α, β and γ), WO 2006/094662 (rifaximin forms δ and ε), WO 2009/108730 (form ζ, form γ−1(ζ), form η, form α-dry, form {acute over (ι)}, form β−1, form β−2, form ε-dry and various amorphous forms of rifaximin having characteristic X-ray diffraction peaks). U.S. Pat. No. 7,709,634 and WO 2008/035109 describe further amorphous forms of rifaximin.
Some technical and/or pharmaceutical properties such as solubility, intrinsic dissolution, bioavailability are reported only for some of the crystalline forms of rifaximin described in the literature. In particular, such information are available for rifaximin polymorphic forms α, β, γ, δ, ε and amorphous form.
Crystalline forms of rifaximin containing organic solvents are known, for instance WO 2009/108730 describes the form β−1, with an ethanolate/trihydrate of rifaximin.
WO 2012/150561 describes a solvate of rifaximin with N,N-dimethylformamide (DMF).
WO 2012/156951 describes a crystal of rifaximin κ obtained in presence of 1,2 dimethyl ether (DME).
The presence of organic solvents in the crystalline forms of rifaximin should be carefully monitored in medicinal products. Certain organic compounds have proven to be toxic for both humans and animals, leading health authorities to set maximum acceptable limits for these substances in products administered to humans.
For example, ethanol and DMF are organic solvents and their use in pharmaceutical compounds is regulated by European Guideline for residual solvent (CPMP/ICH/283/95). These guidelines divide organic solvents into three classes: Class 1, solvents which must be avoided; Class 2, solvents having an administration upper limit; Class 3, solvents with a low toxic potential, but having a maximum permitted daily dose (permitted daily exposure, PDE).
DMF, comprised in rifaximin κ as described in WO 2012/150561, belongs to the Class 3 and has a PDE of 8.8 mg. Taking into account that rifaximin-based pharmaceuticals can in some instances be administered in doses up to 2400 mg/die (Lorenzetti R. et al., Clin. Invest 2013, 3(12), 1187-1193), it must contain an amount corresponding to a rifaximin-DMF molar ratio larger than about 23:1 in order to keep the DMF exposure below the limit of 8.8 mg/die.
Although WO 2012/150561 does not explicitly mention the molar ratio between rifaximin and DMF, the described crystal contains at least one DMF mole for each rifaximin mole; in this case, the weight ratio between the two components would be 11:1, and consequently for a daily rifaximin dosage of 2400 mg, the DMF amount would be much larger than the safety limit permitted for this compound.
A similar case is represented by the crystalline form β−1, described in WO 2009/108730, containing ethanol, which has a PDE of 50 mg/die. Since the molar ratio reported between rifaximin and ethanol in crystalline form β−1 is 1:1, when rifaximin is administered at 2400 mg/die, the administered ethanol amount is about 141 mg/die, namely larger that the permitted amount for Class 3. Therefore, this crystalline form is also potentially toxic.
DME, described in WO 2012/156951 for the preparation of rifaximin κ, is a gaseous compound at room temperature, usually used as propeller and fuel, and should be avoided in industrial processes. Moreover, exposure to DME can have toxic effects, and it is reported that the exposure of pregnant rats to environments containing 1000 ppm DME has showed toxic effects both on the foetus and on the mother and studies on the exposure of rats and dogs showed cardiac arrhythmia and sedative effects as reported in Dupon Technical Information for 1,2 dimethyl ether (Dymel®).
All these observations lead to the conclusion that DME is potentially a toxic compound and its use in pharmaceutical preparations must be avoided. DME is easily inflammable and explosive and its potential industrial use for the preparation of rifaximin polymorphs is problematic.
The polymorphic form and the morphology of a solid form of a pharmaceutical compound can affect its physicochemical and biological properties. Therefore it is important and useful to search new forms of a known compound that can be effectively and safely administered for medical use at a lower dosage and/or possess a different absorption profile in humans and animals. It is also important to find pharmaceutical preparations obtainable by industrial process.
The present invention describes a new crystalline form of rifaximin called rifaximin τ, which comprises in its crystalline structure, the compound identified by IUPAC nomenclature as 2-(2-ethoxyethoxy)ethanol, also known as diethylene glycol monoethyl ether, (DEGME), commercially available as a product under the trade name Transcutol® or Carbitol®.
The new crystalline form is a solvated stoichiometric form of rifaximin with a rifaximin:DEGME molar ratio of 1:1.
DEGME is a compound commonly used in the pharmaceutical industry and approved as a pharmaceutical excipient for its safety, and therefore easily usable. Several studies have shown that, per oral route, the NOAEL (No Observed Adverse Effect Level) value for DEGME is higher than about 160 mg/kg of body mass (European Commission, Health & Consumer Protection Directorate—General; Scientific Committee on Consumer Products [SCCP], Opinion on Diethylene Glycol Monoethyl ether [DEGME], 19 Dec. 2006). It follows that, in the case of a patient having a body weight of 70 kg, the DEGME daily administrable amount with no observed adverse effect is about 11200 mg. As a safety precaution, it is generally recommended that a toxic substance be administered at a dosage at least ten times lower than NOAEL; therefore, in the case of DEGME, doses lower than 1110 mg/die are deemed within the safe range. Where the molar ratio of rifaximin τ to DEGME is 1:1, this amount would correspond to a rifaximin dose of 6500 mg/die, which is higher than the typical dosages required in the pathologies treated with rifaximin.
Rifaximin τ is a stable form, and the crystalline structure does not transform when it is exposed to a humid environment at varying levels of humidity.
Rifaximin τ is a crystalline form of rifaximin with increased solubility in comparison with other crystalline forms, which provides high rifaximin concentrations in aqueous solution, maintaining a low absorption and avoiding systemic exposure. Said rifaximin τ does not show a proportional correspondence between solubility in aqueous solution and in vivo bioavailability values. The present invention also describes the process for obtaining the crystalline form of rifaximin τ, the pharmaceutical compositions comprising said form and their use in the treatment and/or prevention of infections and inflammations.